Ligand-Controlled Selectivity in the Pd-Catalyzed C–H/C–H Cross-Coupling of Indoles with Molecular Oxygen

• DOI: 10.1021/acscatal.0c04893
• Publication Date: 2021-02-10T04:10:44Z
• Authors: Igor Beckers; Besir Krasniqi; Prashant Kumar; Daniel Escudero; Dirk De Vos
• Keywords: Hammett study; Chemical Sciences not elsewhere classified; synthesis; Immunology; Biophysics; substitution patterns; Biochemistry; 01 natural sciences; N-substituted indoles; Ligand-Controlled Selectivity; cross-coupling; insulin-like growth factor inhibitor; C-H activation; Molecular Biology; Cancer; Evolutionary Biology; Science & Technology; Chemistry, Physical; Cell Biology; Transition metals; palladium; homogeneous catalysis; reaction steps; 3. Good health; 0104 chemical sciences; Chemistry; indole; Molecular Oxygen; Physical Sciences; Medicine; C-C coupling; oxygen; carboxylate ligands; Biotechnology

Two indoles linked by a C–C bond have recently emerged as promising scaffolds in medicinal chemistry. Their synthesis, however, involves multitude of reaction steps. So far, the direct C–H/C–H cross-coupling two similar heteroaromatics lacking directing groups remains particularly challenging. Transition metals are often added wasteful sacrificial oxidants to influence selectivity Pd-catalyzed couplings. In this work, we report on selective N-substituted without groups, driven molecular oxygen under mild conditions. The C–H activations was studied via kinetic experiments and computational investigations. A quantitative Hammett study aromatic carboxylate ligands shows that regioselectivity can be directed rationally tuning their electronic properties. This ligand-controlled exploited obtain between with different substitution patterns, demonstrated synthesis potent insulin-like growth factor inhibitor.